Indian Journal of Critical Care Medicine Medknow Publications on behalf of the Indian Society of Critical Care Medicine ISSN: 0972-5229 EISSN: 1998-359x Vol. 9, Num. 1, 2005, pp. 11-13

Indian Journal of Critical Care Medicine, Vol. 9, No. 1, January-March, 2005, pp. 11-13

Editorial

Recombinant activated factor VII for acute intracerebral hemorrhage

Kumar Sudhir

Neurology Department, Apollo Hospitals, Jubilee Hills, Hyderabad - 500 033
Correspondence Address: Consultant Neurologist, Neurology Department, Apollo Hospitals, Jubilee Hills, Hyderabad - 500 033, E-mail: drsudhirkumar@yahoo.com

Code Number: cm05001

Acute stroke is the third leading cause of death worldwide, exceeded only by coronary artery disease and cancer.[1] There are two major subtypes of stroke- ischemic and hemorrhagic with 20-30% of all strokes being hemorrhagic in nature.[2] The incidence of ischemic strokes has steadily declined by virtue of rigorous risk factor modification, but the same has not been possible for hemorrhagic strokes. Moreover, ischemic strokes can now be effectively treated by thrombolysis with tissue plasminogen activator. On the other hand, the incidence of intracerebral hemorrhage (ICH) is expected to grow, given the aging of the population. The treatment of hemorrhagic strokes remains mainly conservative with a recent large multi-centric study failing to show any benefit from early surgery[2] and the mortality at 30 days is seven times higher than ischemic strokes (63% vs. 9%).[3] However, it is believed that strict control of hypertension may significantly decrease the incidence of nonlobar type of ICH.[4] The above factors clearly point towards the need for newer drugs or treatment modalities for patients with ICH. Recombinant activated factor VII (rFVIIa), as shown in some recent trials, appears to be of promise in the management of ICH.[5]

Rationale for using rFVIIa in ICH

Historically, bleeding due to a hemorrhagic stroke was considered to be a monophasic event that stopped quickly as a result of clotting and tamponade by the surrounding brain tissue. However, computerized tomography-based studies have demonstrated that the initial hematoma expands in up to 38% of patients who were initially scanned within 3 hours of the onset of stroke, and in 16% of those scanned between 3 and 6 hours, even in the absence of coagulopathy.[6] Progressive bleeding of this type has been associated with contrast extravasation on CT angiography[7] and poor outcome after early (<4 hours) surgical clot evacuation.[8] On the basis of these observations, it is plausible that ultra-early hemostatic therapy given in the emergency room setting might improve outcome after ICH by arresting ongoing bleeding and minimizing the increase in the volume of the hematoma. rFVIIa is approved to treat bleeding in patients with hemophilia who have antibodies to factor VIII or IX, and it has been reported to reduce bleeding in patients without coagulopathy as well.[9]

The precise mechanism by which rFVIIa arrests bleeding in patients with acute ICH is not fully understood. It promotes hemostasis by activating the extrinsic pathway of the coagulation cascade. After blood-vessel damage and local initiation of the coagulation cascade, the administration of rFVIIa enhances thrombin generation on the surface of activated platelets, leading to accelerated formation of a fibrin clot.[10] It seems most likely that the administration of rFVIIa after ICH accelerates thrombosis within ruptured small penetrating arteries or arterioles. Although the half-life of rFVIIa is only 2.6 hours, a sustained hemostatic effect may occur after a single dose because the clot that forms is denser than normal and more resistant to fibrinolysis.[11]

Current evidence regarding the efficacy of rFVIIa in ICH

rFVIIa for spontaneous ICH in adults
In a recent multi-centre, double-blind, placebo-controlled trial, 399 adult patients with CT-documented ICH were randomized to receive either placebo or rFVIIa (at a dose of 40, 80 or 160 mg per kilogram body weight) as a single intravenous dose within four hours of onset of symptoms (within one hour of CT).[5] There was a greater increase in hematoma volume in the placebo group than in the rFVIIa groups. The mean increase was 29% in the placebo group, as compared with 16%, 14%, and 11% in the groups given 40 mg, 80 mg, and 160 mg of rFVIIa per kilogram, respectively. Growth of the hematoma was reduced by 3.3 ml, 4.5 ml, and 5.8 ml in the three treatment groups, as compared with that in the placebo group. Outcome at 90 days was worse in the placebo group. Sixty-nine percent of placebo-treated patients died or were severely disabled, as compared with 55%, 49%, and 54% of the patients who were given 40, 80, and 160 µg of rFVIIa, respectively. Mortality was 29% for patients who received placebo, as compared with 18% in the three rFVIIa groups combined. This study, therefore, establishes the efficacy of rFVIIa in ICH, if administered within four hours of symptom onset.

Role of rFVIIa in patients with ICH on warfarin thromboprophylaxis
Major bleeding is a frequent and hazardous complication associated with thromboprophylaxis using vitamin-K antagonists (VKA) such as warfarin. Suggested regimens for control of the elevated International Normalized Ratio (INR) and hemorrhagic events during VKA treatment include administration of vitamin K, infusion of fresh frozen plasma or a prothrombin complex concentrate. However, correction of INR by these measures may take 24-48 hours; and for the patients who require an emergent neurosurgical intervention and evacuation of hematoma, early normalization of INR would be a distinct advantage. In a study on seven patients with oral-anticoagulant induced ICH (INR ranging from 1.7 to 6.6) requiring emergency neurosurgical intervention, rFVIIa was administered at a dose of 10-40 mg/kg body weight,[12] which resulted in a reduction in the INR to 1.5 or less within 10 minutes of administration of rFVIIa. Six patients underwent drainage of the hematoma and survived to hospital discharge.

rFVIIa therapy for ICH in patients with hemophilia A or B with inhibitors
The efficacy of rFVIIa for ICH in hemophilia A patients with inhibitors was demonstrated more than a decade ago in a study on five patients.[13] More recently, in a study on 12 patients with hemophilia and life-threatening ICH previously unresponsive to one or more alternate therapies; rFVIIa was administered in an emergency setting,[14] resulting in effective ICH control in 10 patients.

rFVIIa therapy in thrombocytopenic patients with ICH
Efficacy of rFVIIa in thrombocytopenic patients with ICH has been demonstrated with a few case reports.[15],[16] The clinical settings included patients with refractory thrombocytopenia or idiopathic thrombocytopenic purpura, who required emergency surgery and therapies with platelet rich concentrates or intravenous immunoglobulins had failed.

rFVIIa for cerebral-injury induced coagulopathy
Coagulopathy is common in patients with moderate or severe head injury. In a recent study, thrombocytopenia and coagulopathy were present in 14% and 21% of patients at admission, which increased to 46% and 41% by the third day.[17] Many patients with head injury require emergency neurosurgical intervention including evacuation of intracerebral hematoma and placement of intracranial pressure monitoring devices. The procedures may get delayed in presence of coagulopathy. In this setting, therapy with rFVIIa could be useful. In a study on three pediatric patients, rFVIIa at a dose of 90 mg/kg body weight was found to be effective in correcting the coagulopathy and allowing the neurosurgical procedures without any complication.[18]

Adverse events with rFVIIa therapy

Dose, availability and cost

Summary

References

Copyright 2005 - Indian Journal of Critical Care Medicine